Sensitivity to cigarette smoke-induced COPD is highly variable. Many genetic and environmental factors[unreadable] that are thought to be responsible for this natural variation, however, remain unidentified. Our preliminary[unreadable] results suggest that the level of elastin in the lung is critical for normal lung development and for timely and[unreadable] efficient repair following injury. When elastin levels are below a critical threshold, repair is unproductive and[unreadable] the lungs are more prone to develop COPD. Moreover, we have found that patients with mutations in the[unreadable] elastin gene (ELN) develop severe, very early onset bronchiectasis, emphysema and end-stage lung[unreadable] disease. Rare variants of elastin could also predispose to enhanced lung damage by affecting the quality of[unreadable] the elastic fiber. In this case, minor alterations in elastin processing or assembly could support normal lung[unreadable] development and function but result in fibers that have increased susceptibility to degradation by proteases.[unreadable] The central hypothesis of this proposal is that the quality and quantity of pulmonary elastin is a critical[unreadable] factor in determining susceptibility to cigarette smoke-induced lung damage, leading to COPD. This[unreadable] hypothesis is supported by preliminary data indicating that both quantitative and qualitative deficiency in[unreadable] elastin can predispose to smoke-induced emphysema in both animal models and in inherited syndromes in[unreadable] humans caused by ELN mutations. The goal of this proposal is to uncover the mechanisms by which elastin[unreadable] defects result in COPD, and to assess mutations and variants in ELN as risk factors of COPD. To achieve[unreadable] these goals we propose the following specific aims: Aim 1. To test if human genetic diseases caused by[unreadable] mutations in ELN are associated with an increased risk of COPD. Aim 2. To test whether genetic variants[unreadable] present in the normal population (a) alter ELN function and (b) are associated with quantitative outcome[unreadable] measures in patients with severe emphysema. Aim 3: To test if lower than normal levels of lung elastin[unreadable] resulting from genetic or environmental factors lead to increased susceptibility to COPD. Aim 4. To test if[unreadable] qualitative alterations in pulmonary elastin arising from rare elastin variants contribute to COPD[unreadable] susceptibility.